Antagonist anti-CD40 monoclonal antibodies and methods for their use

Abstract

Compositions and methods of therapy for treating diseases mediated by stimulation of CD40 signaling on CD40-expressing cells are provided. The methods comprise administering a therapeutically effective amount of an antagonist anti-CD40 antibody or antigen-binding fragment thereof to a patient in need thereof. The antagonist anti-CD40 antibody or antigen-binding fragment thereof is free of significant agonist activity, but exhibits antagonist activity when the antibody binds a CD40 antigen on a human CD40-expressing cell. Antagonist activity of the anti-CD40 antibody or antigen-binding fragment thereof beneficially inhibits proliferation and/or differentiation of human CD40-expressing cells, such as B cells.

That which is claimed is: 
     
       1. A method for inhibiting growth or differentiation of a normal human B cell, or for inhibiting proliferation of a normal human B cell wherein said proliferation is augmented by the interaction of CD40 ligand with CD40 expressed on the surface of said B cell, comprising contacting said B cell with an effective amount of a human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of said B cell, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
 
 e) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 f) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:2, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:4; 
 g) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-f), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 h) a conjugated form of the monoclonal antibody of any one of preceding items a)-g); 
 said monoclonal antibody being free of significant agonist activity, and whereby when said antibody binds to said CD40 antigen on said B cell, the growth or differentiation of said B cell is inhibited. 
 
     
     
       2. A method for inhibiting antibody production by B cells in a human patient, comprising administering to a human patient an effective amount of a human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing B cells, where said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
 
 e) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 f) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:2, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:4; 
 g) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-f), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 h) a conjugated form of the monoclonal antibody of any one of preceding items a)-g); 
 said monoclonal antibody being free of significant agonist activity, and whereby when said antibody binds to said CD40 antigen on said B cell, the growth or differentiation of said B cell is inhibited. 
 
     
     
       3. A method for reducing one or more symptoms of an inflammatory disease or autoimmune disease in a human subject in need thereof, wherein said one or more symptoms are mediated by stimulation of CD40-expressing cells by CD40 ligand binding to CD40 on said cells in said human subject, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said CD40-expressing cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
 
 e) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-d), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 f) a conjugated form of the monoclonal antibody of any one of preceding items a)-e). 
 
     
     
       4. The method of  claim 3 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       5. The method of  claim 3 , wherein said monoclonal antibody is recombinantly produced in a Chinese Hamster Ovary (CHO) cell line. 
     
     
       6. The method of  claim 3 , wherein said inflammatory disease or autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), discoid lupus, lupus nephritis, sarcoidosis, juvenile arthritis, rheumatoid arthritis, psoriatic arthritis, Reiter's syndrome, ankylosing spondylitis, gouty arthritis, rejection of an organ or tissue transplant, graft versus host disease, multiple sclerosis, hyper IgE syndrome, polyarteritis nodosa, primary biliary cirrhosis, inflammatory bowel disease, Crohn's disease, celiac's disease (gluten-sensitive enteropathy), autoimmune hepatitis, pernicious anemia, autoimmune hemolytic anemia, psoriasis, scleroderma, myasthenia gravis, autoimmune thrombocytopenic purpura, autoimmune thyroiditis, Grave's disease, Hashimoto's thyroiditis, immune complex disease, chronic fatigue immune dysfunction syndrome (CFIDS), polymyositis and dermatomyositis, cryoglobulinemia, thrombolysis, cardiomyopathy, pemphigus vulgaris, pulmonary interstitial fibrosis, sarcoidosis, Type I and Type II diabetes mellitus, type 1, 2, 3, and 4 delayed-type hypersensitivity, allergy or allergic disorders, asthma, Churg-Strauss syndrome (allergic granulomatosis), atopic dermatitis, allergic and irritant contact dermatitis, urtecaria, IgE-mediated allergy, atherosclerosis, vasculitis, idiopathic inflammatory myopathies, hemolytic disease, Alzheimer's disease, and chronic inflammatory demyelinating polyneuropathy. 
     
     
       7. A method for treating a human subject for transplant rejection, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
 
 e) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-d), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 f) a conjugated form of the monoclonal antibody of any one of preceding items a)-e). 
 
     
     
       8. The method of  claim 7 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       9. The method of  claim 7 , wherein said monoclonal antibody is recombinantly produced in a Chinese Hamster Ovary (CHO) cell line. 
     
     
       10. The method of  claim 7 , wherein said treatment further comprises administering an immunosuppressive agent in a pharmaceutically acceptable excipient. 
     
     
       11. The method of  claim 10 , wherein the immunosuppressive agent is selected from the group consisting of cyclosporine, FK506, rapamycin, corticosteroids, CTLA4-Ig, and anti-B Lymphocyte Stimulator antibody. 
     
     
       12. A method for treating a human subject for rheumatoid arthritis, comprising administering an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
 
 e) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-d), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 f) a conjugated form of the monoclonal antibody of any one of preceding items a)-e). 
 
     
     
       13. The method of  claim 12 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       14. The method of  claim 12 , wherein said monoclonal antibody is recombinantly produced in a Chinese Hamster Ovary (CHO) cell line. 
     
     
       15. The method of  claim 12 , wherein said treatment further comprises administering an immunosuppressive agent in a pharmaceutically acceptable excipient. 
     
     
       16. The method of  claim 15 , wherein the immunosuppressive agent is selected from the group consisting of cyclosporine, FK506, rapamycin, corticosteroids, CTLA4-Ig, an anti-CD20 antibody, and anti-B Lymphocyte Stimulator antibody. 
     
     
       17. The method of  claim 3 , further comprising combination therapy with at least one other therapy for said inflammatory disease or autoimmune disease, wherein said at least one other therapy is administered to said human subject prior to, during, or subsequent to administration of said antagonist anti-CD40 monoclonal antibody. 
     
     
       18. The method of  claim 17 , wherein said at least one other therapy is selected from the group consisting of: surgery, organ perfusion, radiation therapy, steroid therapy, non-steroidal therapy, antibiotic therapy, antifungal therapy, hormone therapy, cytokine therapy, therapy with dermatological agents, immunosuppressive therapy, and other anti-inflammatory monoclonal antibody therapy. 
     
     
       19. A method for inhibiting a CD40 ligand-mediated CD40 signaling pathway in a normal human CD40-expressing cell, said method comprising contacting said cell with an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of said cell, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
 
 e) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 f) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:2, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:4; 
 g) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-f), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 h) a conjugated form of the monoclonal antibody of any one of preceding items a)-g). 
 
     
     
       20. The method of  claim 19 , wherein said normal human CD40-expressing cell is a normal human B cell and said CD40 signaling pathway is B cell survival. 
     
     
       21. The method of  claim 1 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       22. The method of  claim 2 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       23. The method of  claim 19 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       24. A method for reducing one or more symptoms of an inflammatory disease or autoimmune disease in a human subject in need thereof, wherein said one or more symptoms are mediated by stimulation of CD40-expressing cells by CD40 ligand binding to CD40 on said cells in said human subject, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said CD40-expressing cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:2, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:4; 
 b) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 c) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of preceding item a) or b), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       25. The method of  claim 24 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       26. A method for reducing one or more symptoms of an inflammatory disease or autoimmune disease in a human subject in need thereof, wherein said one or more symptoms are mediated by stimulation of CD40-expressing cells by CD40 ligand binding to CD40 on said cells in said human subject, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said CD40-expressing cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543 or an antigen-binding fragment thereof, wherein said fragment retains the capability of specifically binding to said human CD40; and 
 b) a conjugated form of the monoclonal antibody or antigen-binding fragment of preceding item a). 
 
     
     
       27. The method of  claim 26 , wherein said antigen-binding fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       28. A method for reducing one or more symptoms of an inflammatory disease or autoimmune disease in a human subject in need thereof, wherein said one or more symptoms are mediated by stimulation of CD40-expressing cells by CD40 ligand binding to CD40 on said cells in said human subject, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said CD40-expressing cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 b) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 c) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       29. A method for treating a human subject for transplant rejection, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:2, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:4; 
 b) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 c) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of preceding item a) or b), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       30. The method of  claim 29 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       31. A method for treating a human subject for transplant rejection, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543 or an antigen-binding fragment thereof, wherein said fragment retains the capability of specifically binding to said human CD40; and 
 b) a conjugated form of the monoclonal antibody or antigen-binding fragment of preceding item a). 
 
     
     
       32. The method of  claim 31 , wherein said antigen-binding fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       33. A method for treating a human subject for transplant rejection, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 b) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 c) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       34. A method for treating a human subject for rheumatoid arthritis, comprising administering an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:2, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:4; 
 b) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543; 
 c) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of preceding item a) or b), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       35. The method of  claim 34 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       36. A method for treating a human subject for rheumatoid arthritis, comprising administering an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543 or an antigen-binding fragment thereof, wherein said fragment retains the capability of specifically binding to said human CD40; and 
 b) a conjugated form of the monoclonal antibody or antigen-binding fragment of preceding item a). 
 
     
     
       37. The method of  claim 36 , wherein said antigen-binding fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       38. A method for treating a human subject for rheumatoid arthritis, comprising administering an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 b) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 c) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       39. A method for inhibiting growth or differentiation of a normal human B cell, or for inhibiting proliferation of a normal human B cell wherein said proliferation is augmented by the interaction of a CD40 ligand with a CD40 expressed on the surface of said B cell, comprising contacting said B cell with an effective amount of a human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of said B cell, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
 
 e) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 f) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:6, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:7; 
 g) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-f), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 h) a conjugated form of the monoclonal antibody of any one of preceding items a)-g); 
 said monoclonal antibody being free of significant agonist activity, and whereby when said antibody binds to said CD40 antigen on said B cell, the growth or differentiation of said B cell is inhibited. 
 
     
     
       40. The method of  claim 39 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       41. A method for inhibiting antibody production by B cells in a human patient, comprising administering to a human patient an effective amount of a human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing B cells, where said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
 
 e) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 f) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:6, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:7; 
 g) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-f), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 h) a conjugated form of the monoclonal antibody of any one of preceding items a)-g); 
 said monoclonal antibody being free of significant agonist activity, and whereby when said antibody binds to said CD40 antigen on said B cell, the growth or differentiation of said B cell is inhibited. 
 
     
     
       42. The method of  claim 41 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       43. A method for reducing one or more symptoms of an inflammatory disease or autoimmune disease in a human subject in need thereof, wherein said one or more symptoms are mediated by stimulation of CD40-expressing cells by CD40 ligand binding to CD40 on said cells in said human subject, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said CD40-expressing cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
 
 e) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-d), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 f) a conjugated form of the monoclonal antibody of any one of preceding items a)-e). 
 
     
     
       44. The method of  claim 43 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       45. The method of  claim 43 , wherein said antibody is produced in a Chinese Hamster Ovary (CHO) cell line. 
     
     
       46. A method for reducing one or more symptoms of an inflammatory disease or autoimmune disease in a human subject in need thereof, wherein said one or more symptoms are mediated by stimulation of CD40-expressing cells by CD40 ligand binding to CD40 on said cells in said human subject, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said CD40-expressing cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:6, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:7; 
 b) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 c) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of preceding item a) or b), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       47. The method of  claim 46 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       48. A method for reducing one or more symptoms of an inflammatory disease or autoimmune disease in a human subject in need thereof, wherein said one or more symptoms are mediated by stimulation of CD40-expressing cells by CD40 ligand binding to CD40 on said cells in said human subject, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said CD40-expressing cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542 or an antigen-binding fragment thereof, wherein said fragment retains the capability of specifically binding to said human CD40; and 
 b) a conjugated form of the monoclonal antibody or antigen-binding fragment of preceding item a) or b). 
 
     
     
       49. The method of  claim 48 , wherein said antigen-binding fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       50. A method for reducing one or more symptoms of an inflammatory disease or autoimmune disease in a human subject in need thereof, wherein said one or more symptoms are mediated by stimulation of CD40-expressing cells by CD40 ligand binding to CD40 on said cells in said human subject, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said CD40-expressing cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 b) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 c) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       51. A method for treating a human subject for transplant rejection, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
 
 e) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-d), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 f) a conjugated form of the monoclonal antibody of any one of preceding items a)-e). 
 
     
     
       52. The method of  claim 51 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       53. The method of  claim 51 , wherein said antibody is produced in a Chinese Hamster Ovary (CHO) cell line. 
     
     
       54. A method for treating a human subject for transplant rejection, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:6, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:7; 
 b) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 c) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of preceding item a) or b), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       55. The method of  claim 54 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       56. A method for treating a human subject for transplant rejection, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542 or an antigen-binding fragment thereof, wherein said fragment retains the capability of specifically binding to said human CD40; and 
 b) a conjugated form of the monoclonal antibody or antigen-binding fragment of preceding item a). 
 
     
     
       57. The method of  claim 56 , wherein said antigen-binding fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       58. A method for treating a human subject for transplant rejection, said method comprising administering to said subject an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said monoclonal antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 b) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 c) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       59. A method for treating a human subject for rheumatoid arthritis, comprising administering an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
 
 e) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-d), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 f) a conjugated form of the monoclonal antibody of any one of preceding items a)-e). 
 
     
     
       60. The method of  claim 59 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       61. The method of  claim 59 , wherein said antibody is produced in a Chinese Hamster Ovary (CHO) cell line. 
     
     
       62. A method for treating a human subject for rheumatoid arthritis, comprising administering an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said mooclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:6, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:7; 
 b) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 c) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of preceding item a) or b), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       63. The method of  claim 62 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       64. A method for treating a human subject for rheumatoid arthritis, comprising administering an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542 or an antigen-binding fragment thereof, wherein said fragment retains the capability of specifically binding to said human CD40; and 
 b) a conjugated form of the monoclonal antibody or antigen-binding fragment of preceding item a). 
 
     
     
       65. The method of  claim 64 , wherein said antigen-binding fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
       66. A method for treating a human subject for rheumatoid arthritis, comprising administering an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of human CD40-expressing cells, said antibody being free of significant agonist activity when bound to human CD40 expressed on the surface of said cells, wherein said monoclonal antibody is selected from the group consisting of:
 a) a monoclonal antibody comprising residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 b) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 c) a monoclonal antibody comprising residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; and 
 d) a conjugated form of the monoclonal antibody of any one of preceding items a)-c). 
 
     
     
       67. A method for inhibiting a CD40 ligand-mediated CD40 signaling pathway in a normal human CD40-expressing cell, said method comprising contacting said cell with an effective amount of an antagonist human anti-CD40 monoclonal antibody that is capable of specifically binding to human CD40 expressed on the surface of said cell, wherein said monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 b) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6; 
 c) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7; 
 d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
 
 e) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-5.9 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5542; 
 f) a monoclonal antibody comprising a light chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:6, and a heavy chain variable domain containing the complementarity determining region (CDR) residues of SEQ ID NO:7; 
 g) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-f), wherein said fragment retains the capability of specifically binding to said human CD40; and 
 h) a conjugated form of the monoclonal antibody of any one of preceding items a)-g). 
 
     
     
       68. The method of  claim 67 , wherein said normal human CD40-expressing cell is a normal human B cell and said CD40 signaling pathway is B cell survival. 
     
     
       69. The method of  claim 67 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment.